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Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis

酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响

基本信息

批准号：
10676118
负责人：
Gianfranco D Alpini
金额：
$ 53.64万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-05 至 2023-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676118
关键词：
Address Affect Alcohol-Induced Disorders Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcoholic liver damage Alcoholic steatohepatitis Alcohols Animal Model Biliary CCL2 gene CXCL1 gene Cell Line Cells Cholestasis Cholesterol Chronic Cirrhosis Communication Country Data Disease Progression Epithelial Cells Ethanol Fibrosis Genes Hepatic Hepatic Stellate Cell Hepatobiliary Hepatocyte Hepatotoxicity High Fat Diet Human IL8 gene Immune Impairment In Vitro Infiltration Inflammation Inflammatory Injury Kupffer Cells Link Liver Liver Cirrhosis Liver Fibrosis Liver diseases Longitudinal Studies Mediating MicroRNAs Modeling Morbidity - disease rate Mus National Institute on Alcohol Abuse and Alcoholism Nerve Growth Factors Neurosecretory Systems Pathogenesis Pathology Patients Phenotype Play Prevention Primary carcinoma of the liver cells Proliferating Reaction Receptor Signaling Research Role Sampling Secretin Serum Testing Therapeutic Transfection United States Vascular Endothelium alcohol exposure antagonist bile duct cholangiocyte chronic liver disease chronic liver injury cytokine extracellular vesicles feeding human disease insight intrahepatic liver cell proliferation liver inflammation liver injury loss of function mortality mouse model novel pharmacologic prevent problem drinker receptor recruit response secretin receptor senescence simple steatosis stellate cell therapeutic evaluation therapeutic target translational study western diet

项目摘要

Alcohol-associated liver disease (ALD) is a leading cause of chronic liver diseases and the predominant cause of liver-related mortality in Western countries. Patients with ALD may develop a wide spectrum of liver pathologies from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and eventually hepatocellular carcinoma. Extensive research has been performed to study the impact of alcohol on hepatocytes, stellate cells, and immune cells including Kupffer cells in ALD, but little is known about how alcohol affects biliary epithelial cells (i.e., cholangiocytes), and how biliary damage may contribute to the early and late stages of ALD pathogenesis. Recent studies have indicated that ductular reaction occurs in patients with alcoholic hepatitis. We have previously shown in other models of hepatic damage that the secretin (Sct)/secretin receptor (SR) axis is upregulated and plays a critical role in ductular reaction/biliary senescence as well as contributes to hepatic fibrosis. Our preliminary data that ALD-induced ductular reaction, biliary senescence, inflammation, and fibrosis were ameliorated in mice lacking the Sct/SR axis, indicating a crucial role for the SCT/SR axis during the pathogenesis of ALD. We propose the novel central hypothesis that the SCT/SR signaling axis is a key for mediating the senescent, profibrogenic biliary phenotype that contributes to the progression of hepatic inflammatory cell infiltration and subsequent fibrosis during the course of the pathogenesis of ALD. To test our hypothesis, we will pursue the following specific aims. In Specific aim #1, we will determine that activation of SCT/SR axis-dependent ductular reaction and biliary senescence plays a key role in the induction of liver inflammation that drives hepatic fibrosis during the pathogenesis of ALD. In specific aim #2, we will evaluate if therapeutic inhibition of the SCT/SR axis can prevent and limit the progression of ALD. Completion of the proposed studies will elucidate the translational mechanism on the role of SCT/SR axis in the promotion of local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype, biliary senescence, hepatobiliary inflammation and fibrosis during the progression of ALD.

酒精相关性肝病(ALD)是慢性肝病的主要原因之一，也是最主要的在西方国家，与肝脏相关的死亡原因。肌萎缩侧索硬化症患者可能会出现广泛的从单纯性脂肪变性到酒精性脂肪性肝炎(ASH)、酒精性肝炎(AH)、肝硬变、最后是肝细胞癌。已经进行了广泛的研究，以研究酒精对ALD患者肝细胞、星状细胞和免疫细胞(包括Kupffer细胞)的影响，但知之甚少关于酒精如何影响胆管上皮细胞(即胆管细胞)，以及胆管损伤如何在ALD发病的早期和晚期起重要作用。最近的研究表明，导管反应发生在酒精性肝炎患者身上。我们之前已经在其他肝脏模型中显示过促胰液素(SCT)/促胰液素受体(SR)轴上调在小管损伤中的作用反应/胆汁衰老以及导致肝纤维化。我们的初步数据显示，ALD诱导胆管反应、胆管衰老、炎症和纤维化在缺乏胆管的小鼠中得到改善 SCT/SR轴，提示SCT/SR轴在ALD的发病机制中起重要作用。我们建议新的中心假说认为SCT/SR信号轴是调节衰老、促纤维化的关键胆汁表型与肝炎性细胞浸润的进展及随后的 ALD发病过程中的纤维化。为了验证我们的假设，我们将执行以下操作明确的目标。在特定目标#1中，我们将确定SCT/SR轴依赖导管的激活反应和胆汁衰老在导致肝脏炎症的过程中起着关键作用。 ALD发病过程中的纤维化。在特定的目标2中，我们将评估是否治疗抑制 SCT/SR轴可以预防和限制ALD的进展。建议的研究完成后，阐明SCT/SR轴促进局部和全身炎症反应的翻译机制对神经内分泌/促纤维化胆管表型活化、胆管衰老、 ALD进展过程中的肝胆炎症和纤维化。